P390: ACUTE MYELOID LEUKEMIA SUPPRESSION BY PALBOCICLIB AND PONATINIB IN PATIENT-DERIVED XENOGRAFT
Authors: D. Busa, M. Culen, T. Loja, I. Jeziskova, A. Folta, J. Mayer
Journal: HemaSphere (2022)

Background: Palbociclib, a CDK4/6 inhibitor approved for breast cancer treatment, and ponatinib, a BCR/ABL1 inhibitor with a multi-kinase activity approved for chronic myeloid and acute lymphoid leukemia, were previously shown to be effective in vitro against different cancer types including acute myeloid leukemia (AML). Aims: To test palbociclib and ponatinib, along with reference drugs – venetoclax, azacitidine, cytarabine+doxorubicine (chemotherapy) on 2 primary AML samples in a patient-derived xenograft model. Methods: Two newly diagnosed AMLs (AML #1: myelomonocytic AML, intermediate cytogenetic risk; AML #2: AML with myelodysplasia-related changes, poor cytogenetic risk) were xenotransplanted into NOD SCID gamma mice. Treatment was initiated at detection of approximately 5-20% hCD45+ cells in mouse peripheral blood (PB). Chemotherapy (cytarabine+doxorubicine, AraC/Dox) was administered as a 5 + 3 regimen. Azacitidine was administered subcutaneously, five days per week in 3 cycles – 1 week on, 1 week off. Palbociclib, ponatinib, venetoclax, and vehicle were administered orally for 3 weeks, 5 days per week. Gene sequencing was performed using targeted 37 gene Archer Variantplex Core Myeloid Kit panel. Results: From the reference treatments, significant AML reduction and prolonged overall survival (OS) was achieved with venetoclax in both AMLs, and with chemotherapy in AML #1. No statistically significant effect was observed with azacitidine, but interestingly in AML #2 the azacitidine treatment induced the longest remission in the whole study, almost 10 weeks (<1% hCD45+ cells in PB) in 2/4 mice. Of the tested drugs, palbociclib showed the same effect as venetoclax, with significantly reduced AML and prolonged OS in both AMLs. Ponatinib led to prolonged OS only in AML #1 (Fig. 1A-D). Overall, none of the treatments led to complete AML eradication and all PDX groups gradually relapsed. No phenotype changes were observed in the relapsed cells in palbociclib and ponatinib groups compared to vehicle (SSClowCD45dim blasts, SSCdimCD45high monocytes, CD34+ and CD34+CD38- cells). Azacitidine group showed altered monocyte, CD34+, and CD34+CD38- fractions in AML #1. Azacitidine, chemotherapy, and venetoclax showed altered blast and monocyte fraction in AML #2 and venetoclax also altered CD34+ fraction in AML #2. Mutational status in AML #1 remained unchanged (FLT3-TKD and NRAS mutated) in all PDX groups at relapse. In AML #2, KRAS mutation from the primary tumor remained conserved, whereas all PDXs lost an IDH1 mutation and gained a WT1 mutation. This indicates that mutation selection was induced by the xenotransplantation rather than treatment. In addition, a second WT1 mutation was gained only in the palbociclib group. Treatment toxicity manifested by weight decrease after the end of treatment was only seen with chemotherapy and was accompanied by early mouse mortality in 3/4 mice for AML #2. Image:Summary/Conclusion: Palbociclib demonstrated in vivo AML suppression that was comparable to venetoclax and superior to chemotherapy. Effect of ponatinib was only limited. This encourages further investigation of treatment efficacy in different AML subtypes and in combination with other drugs. Funding: MUNI/A/1330/2021